Despite their excellent bioactivity, peptides are rarely good drug candidates because they cannot penetrate cell membrane to reach their intracellular target. A growing number of chemical strategies have been developed recently to convert peptides into cell-permeable bioactive ligands targeting the intracellular protein-protein interactions. These include the use of alternative backbones such as β-peptides, the incorporation of α,α-dialkylamino acids such as Aib, the side chain-to-side chain cross linking via the lactam, hydrocarbon, or heterocyclic bridges, the backbone-to-side chain cross linking; and the use of low molecular weight peptidomimetics such as terphenyl-based helix mimics. Another strategy to impart peptides with improved cell permeability is to fuse peptides with the cell penetrating peptide (CPP) sequences. A drawback to the CPP-fusion approach is that significant mass needs to be added to the peptide.
Though these strategies have generated peptide analogs with the improved cell permeability, extensive chemical modifications were typically required. For example, hydrocarbon cross linking involves the introduction of two chiral α,α-dialkylamino acids carrying the olefin side chains and the subsequent ruthenium-catalyzed ring closing metathesis, which often produces a mixture of Z- and E-olefin linkages.